This invention relates to an improved treatment for cancer comprising administering a combination of at least one camptothecin derivative and at least one other colorectal anticancer drug. More specifically, the invention relates to treatments for colorectal cancer comprising administering a synergistic therapeutically effective combination of Campto(copyright) (CPT-11, Irinotecan), 5-fluorouracil (5-FU), and folinic acid (FA).
Colorectal cancer is a leading cause of morbidity and mortality with about 300,000 new cases and 200,000 deaths in Europe and the USA each year [Boyle P., Some recent developments in the epidemiology of colorectal cancer In: Bleiberg H., Rougier P., Wilke H. J., eds; Management of colorectal cancer London: Martin Dunitz: 19-34 (1998) and Midgley R. S., Kerr D. J., Systemic adjuvant chemotherapy for colorectal cancer In: Bleiberg H., Rougier P., Wilke H. J., eds.; Management of colorectal cancer: London: Martin Dunitz, 126-137 (1998)]. Although about fifty percent of patients are cured by surgery alone, the other half will eventually die due to metastatic disease, which includes approximately 25% of patients who have evidence of metastases at time of diagnosis.
In the United States, there are currently about 130,000 patients with colorectal cancer, 95,000 with colon cancer and 35,000 with rectal cancer. [American Cancer Society. Cancer Facts and Figures 2000.] Of these patients, 20% have metastatic disease at presentation, 40% will ultimately develop metastases, and 57,000 patients will die due to metastatic disease. [Id.].
5-FU has been the mainstay of chemotherapy for colorectal cancer for four decades. It has been shown to improve both survival time (11 months versus 5 months) and quality of life of patients with metastatic disease, when compared to no antitumour therapy [J. Clin. Oncol., 10(6), 904-11 (1992) and Br. Med. J., 306, 752-55 (1993)].
Insights into 5-FU molecular pharmacology have led to several strategies to modulate its cytotoxic effects. Infusional versus bolus administration of 5-FU resulted in a higher response rate (22% v. 14%) but did not significantly effect the median survival time (12.1 months v. 11.3 months). [Meta-analysis Group in Cancer. J. Clin Oncol. 1988; 16:301-308.] The most successful approach has been the coadministration of 5-FU with folinic acid (FA), which increases the degree of inhibition of thymidylate synthase [G. J. Peters, C. L. van der Wilt, C. J. van Groeningen et al; Thymidylate synthase inhibition after administration of fluorouracil with or without Leucovorin in colon cancer patients: implications for treatment with fluorouracil; J. Clin Oncol, 12, no 10: 2035-2042 (1994)], depletes cellular thymidine, and induces apoptosis [C. Benz and E. Cadman; Modulation of 5-fluorouracil metabolism and cytotoxicity by antimetabolite pretreatment in human colorectal adenocarcinoma HCT-8; Cancer Res, 41, 994-999, (1981)]. Folinic acid has been approved in numerous European countries for the treatment of colorectal cancer. Among the various modulations and schedules of administration, high dose infusional regimens of 5-FU plus folinic acid (5-FU/FA) are widely used in Europe and have resulted in the highest response rates (up to 44%) and longest time to progression (around 7 months) and median survival (up to 16.6 months) over administration of bolus 5-FU/FA (J. Clin. Oncol, 15 (2), 808-815 (1997); J. Clin. Oncol, 16(2), 418-426 (1998); Ann of Oncol, (1998); Onkologie, 21,403-307 (1988).
European patent EP 137,145, the disclosure of which is incorporated herein by reference, describes camptothecin derivatives of the formula: 
wherein:
R1 is selected from hydrogen, halogen and alkyl;
X is selected from a chlorine atom and NR2R3, wherein R2 and R3, which may be identical or different, are selected from a hydrogen atom, optionally substituted alkyl radicals, carbocycles and heterocycles which are optionally substituted, and optionally substituted alkyl radicals, and form, with the nitrogen atom to which they are attached, a heterocycle optionally containing another heteroatom selected from O, S and/or NR4, R4 being selected from a hydrogen atom and alkyl radicals; and
wherein the group Xxe2x80x94COxe2x80x94Oxe2x80x94 is located in position 9, 10 or 11 on ring A. These camptothecin derivatives are anticancer agents which inhibit topoisomerase I. CPT-11, also known as Irinotecan, wherein Xxe2x80x94COxe2x80x94Oxe2x80x94 is [4-(1-piperidino)-1-piperidino]carbonyloxy, is a particularly effective agent in the treatment of solid tumors and, in particular, colorectal cancer.
The European patent application EP 74,256, the disclosure of which is incorporated herein by reference, also describes camptothecin derivatives which are mentioned as anticancer agents, in particular derivatives of structures analogous to the structure given above and in which Xxe2x80x94COxe2x80x94Oxe2x80x94 is replaced with a radical xe2x80x94Xxe2x80x2Rxe2x80x2 for which Xxe2x80x2 is O or S and Rxe2x80x2 is a hydrogen atom or an alkyl or acyl radical.
Other camptothecin derivatives have also been described, for example, in the patents or patent applications EP 56,692, EP 88,642, EP 296,612, EP 321,122, EP 325,247, EP 540,099, EP 737,686, WO 90/03169, WO 96/37496, WO 96/38146, WO 96/38449, WO 97/00876, U.S. Pat. No. 7,104,894, JP 57 116,015, JP 57 116,074, JP 59 005,188, JP 60 019,790, JP 01 249,777, JP 01 246,287 and JP 91 012,070 or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego-12-16 April), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul-27 July-1 August), the disclosure of each of these is incorporated herein by reference.
Camptothecin derivatives are usually administered by injection, more particularly intravenously in the form of a sterile solution or an emulsion. Camptothecin derivatives can also be administered orally, in the form of solid or liquid compositions containing the art recognized adjuvants and/or excipients.
CPT-11, a camptothecin-derivative, is one of the most active new agents in colorectal cancer. In patients resistant to 5-FU, single agent CPT-11 tested in two large phase III randomized trials resulted in a longer survival and a better quality of life compared with supportive care only [D. Cunningham, S. Pyrhxc3x6nen, R D. James et al, The Lancet, 352, no 9138, 1413-1418 (1998)]. CPT-11 also resulted in a longer survival without deterioration in quality of life compared with 5-FU/FA infusional regimens [P. Rougier, E. van Cutsem et al The Lancet, 352, no 9138, 1407-1418 (1998)]. CPT-11 has thus been identified as the reference treatment in metastatic colorectal cancer after failure with prior 5-FU treatment.
CPT-11 has also been shown to be at least as active as the so-called standard 5-FUIFA bolus treatment in chemotherapy naive patients with metastatic colorectal cancer. Single-agent CPT-11, administered intravenously at 125 mg/m2 in two separate studies, resulted in a response rate of 32% and 26% respectively. Median survival was 12.1 months and 11.8 months respectively. [J. Clin Oncol, 14(3), 709-715 (1996); J. Clin Oncol, L15(8) 2910-2919(1997)]. Other studies suggest that CPT-11 may extend survival when used as a second-line therapy in combination with either best supportive care or an infusional based 5-FU regimen. [Cunningham et al. The Lancet. 1998; 352; 1413-18; Rougier et al. The Lancet. 1998; 352; 1407-12.]
A study relating to CPT-11 published by D. Cunningham, Eur. J. Cancer, 32A suppl. 3: S1-8 (1996) suggests that CPT-11 offers a different cytotoxic approach, topoisomerase I inhibition, that may complement the use of 5-FU/folinic acid in colorectal cancer in the future.
In addition, combinations of CPT-11 and 5-FU have already been studied in phase I studies in Japan, indicating in preliminary results that concurrent administration is feasible in terms of safety [L. Saltz et al., Eur. J. Cancer 32A, suppl 3 : S24-31 (1996); Saltz, J. Clin Oncol. 1996, 14:2959-2967; Ducreux, J. Clin Oncol. 1999, 17:2901-08; Vanhoefer, J Clin Oncol. 1999, 17:907-13]. At the present time, however, it has never been reported that combinations of CPT-11 and 5-FU can lead to a significant, even therapeutically synergistic increase, of efficacy in the treatment of cancer.